The central role of the neutrophil in ischaemic/reperfusion injury

Inadequate blood flow to an organ, ischaemia, may lead to both local and remote tissue injury characterized by oedema, increased microvascular permeability to protein and degradation of connective tissue components. This damage is probably caused by the accumulation and inappropriate activation of neutrophils which occurs when the tissue is reperfused. To test this hypothesis a number of in vitro models of the sequential stages of ischaemia/reperfusion injury were examined. Methods were initially developed to examine the adhesion of neutrophils to monolayers of a cultured endothelial cell line (ECV304) after periods of hypoxia and reoxygenation. Neutrophil migration in response to factors secreted by the treated endothelial cells was then assessed. The genesis of an inappropriate oxidative burst by the neutrophil upon exposure to endothelial chemoattractants and adhesion molecules was also measured. Finally to appraise how tissue function might be affected by endothelial cell hypoxia the contractility of vascular smooth muscle was examined. Neutrophil adhesion to ECV304 cells, which had been hypoxic for 4 hours and then reoxygenated for 30 minutes, was significantly increased. This response was probably initiated by reactive oxygen species (ROS) generated by the endothelial cells. Blockage of their production by allopurinol reduced the heightened adhesion. Similarly removal of ROS by superoxide dismutase or catalase also attenuated adhesion. ROS generation in turn caused the release of a soluble factor (s) which induced a conformational change on the neutrophil surface allowing it to bind to the intercellular adhesion molecule 1 (ICAM-1) on the endothelial cell. Soluble factor (s) from hypoxia/reoxygenated endothelial cells also had a powerful neutrophil chemoattractant ability. When neutrophils were exposed to both hypoxic/reoxygenated endothelial cells and the soluble factor (s) released by them a large oxidative burst was elicited. This response was greatest immediately after reoxygenation and one hour later was diminishing suggesting at least one of the components involved was labile. Analysis of the supernatant from hypoxic/reoxygenated endothelial cell cultures and studies using inhibitors of secretion suggested platelet activating factor (PAF) may be a major component in this overall sequence of events. Lesser roles for IL-8, TNF and LTB4 were also suggested. The secretory products from hypoxia/reoxygenated endothelial cells also affected smooth muscle contractility having an anti-vasoconstrictor or relaxation property, similar to that exerted by PAF.

A study of the role of the community pharmacist in responding to symptons

Factors affecting the current role of the community pharmacist in responding to symptoms are investigated. Communication and collaboration with general medical practitioners (GPs), and the competency of pharmacists and counter assistants to perform the role of responding to symptoms, are examined. A national survey of GPs, conducted by postal questionnaire, explores attitudes towards the role of the community pharmacist in the treatment of patients' symptoms, and towards future extension of such a role. A majority (over 90%) of respondents thought that the counter prescribing activities of the pharmacist should be maintained or increased. Doctors supported treatment of most minor illnesses by pharmacists, but there was relatively little support for the deregulation of selected Prescription Only Medicines. Three quarters of respondents were in favour of joint educational meetings for pharmacists and doctors. Most GPs (85%) expressed support for a formal referral route from pharmacists to doctors, using a "notification card". A pilot study of the use of a notification card was conducted . Two thirds of the patients who were advised to see their doctor by the pharmacist subsequently did so. In most cases , the GP rated the patients' symptoms " significant" and the card "helpful". Pharmacists' and counter assistants' competency in responding to symptoms was assessed by a programme of pharmacy visits, where previously-defined symptoms were presented. Some pharmacists' questioning skills were found to be inadequate, and their knowledge not sufficiently current. Counter assistants asked fewer and less appropriate questions than did pharmacists, and assistants ' knowledge base was shown to be inadequate. Recommendations are made in relation to the education and training of pharmacists and counter assistants in responding to symptoms .

The role of the cortical occipital spike in photosensitive epilepsy

Chapters one to three are an introduction to photosensitive epilepsy, electroencephalography (EEG) and the magnocellular and parvocellular visual pathways. Photoparoxysmal response (PPR) are strongly associated with photosensitive epilepsy. Chapters four to nine investigated whether occipital spikes were associated with PPR and hence with photosensitive epilepsy. The chapters investigated whether the response types showed similar dependence on stimulus characteristics using EEG. Chapters four and five found that occipital spikes and PPR showed different dependence on colour and luminance contrast. The differences were consistent with the magnocellular pathway mediating occipital spikes and the pavocellular pathway mediating PPR. The study in chapter eight found that monocular occlusion had a significantly greater effect on PPR than on occipital spikes, which is further evidence against an association between the two types of response. Chapters six and seven showed that occipital spikes and PPR had similar optimum spatial and temporal frequencies. Chapter nine showed that both response types could be generated via stimulation of the periphery of the retina. However, these three chapters are not strong evidence of an association, as the results do not contradict the theory that the responses are generated via different pathways. The magnocellular and pavocellular pathways have similar optimum temporal and spatial frequencies and both are present in the periphery. In chapter ten, magnetoencephalography was used to estimate the source of activity underlying the components of the VEP and occipital spike. Changes in the amplitude and latency in the components of the normal VEP are associated with epilepsy. However, the source underlying the occipital spikes was not related to that underlying the components of the VEP so this is also removed as a source of evidence for an association between occipital spikes and photosensitive epilepsy.

The role of the English language in the context of national development vision 2025 with specific reference to agriculture in Tanzania

After thirty years of vacillation, the Tanzanian government has made a firm decision to Swahilize its secondary education system. It has also embarked on an ambitious economic and social development programme (Vision 2025) to transform its peasant society into a modern agricultural community. However, there is a faction in Tanzania opposed to Kiswahili as the medium of education. Already many members of the middle and upper class their children to English medium primary schools to avoid the Kiswahili medium public schools and to prepare their children for the English medium secondary system presently in place. Within the education system, particularly at university level, there is a desire to maintain English as the medium of education. English is seen to provide access to the international scientific community, to cutting edge technology and to the global economy. My interest in this conflict of interests stems from several years' experience teaching English to students at Sokoine University of Agriculture. Students specialise in agriculture and are expected to work with the peasant population on graduation. The students experience difficulties studying in English and then find their Kiswahili skills insufficient to explain to farmers the new techniques and technologies that they have studied in English. They are hampered by a complex triglossic situation in which they use their mother tongue with family and friends, Kiswahili, the national language for early education and most public communication within Tanzania, and English for advanced studies. My aim in this thesis was - to study the language policy in Tanzania and see how it is understood and implemented; - to examine the attitudes towards the various languages and their various roles; - to investigate actual language behaviour in Tanzanian higher education. My conclusion is that the dysfunctionality of the present study has to be addressed. Diglossic public life in Tanzania has to be accommodated. The only solution appears to be a compromise, namely a bilingual education system which supports from all cases of society by using Kiswahili, together with an early introduction of English and its promotion as a privileged foreign language, so that Tanzania can continue to develop internally through Kiswahili and at the same time retain access to the globalising world through the medium of English.

The role of the extracellular loops of the CGRP receptor, a family B GPCR

The CGRP (calcitonin gene-related peptide) receptor is a family B GPCR (G-protein-coupled receptor). It consists of a GPCR, CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activity-modifying protein 1). RAMP1 is needed for CGRP binding and also cell-surface expression of CLR. There have been few systematic studies of the ECLs (extracellular loops) of family B GPCRs. However, they are likely to be especially important for the interaction of the N-termini of the peptide agonists that are the natural agonists for these receptors. We have carried out alanine scans on all three ECLs of CLR, as well as their associated juxtamembrane regions. Residues within all three loops influence CGRP binding and receptor activation. Mutation of Ala203 and Ala206 on ECL1 to leucine increased the affinity of CGRP. Residues at the top of TM (transmembrane) helices 2 and 3 influenced CGRP binding and receptor activation. L351A and E357A in TM6/ECL3 reduced receptor expression and may be needed for CLR association with RAMP1. ECL2 seems especially important for CLR function; of the 16 residues so far examined in this loop, eight residues reduce the potency of CGRP at stimulating cAMP production when mutated to alanine.

Role of the transgenic human thyrotropin receptor A-subunit in thyroiditis induced by A-subunit immunization and regulatory T cell depletion

Transgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (Treg) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A–Z). In transgenic and WT mice, regardless of Treg depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After Treg depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4+ T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA–d). High affinity subsequences (inhibitory concentration of 50% < 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.

The role of the sales employee in securing customer satisfaction

Purpose: Previous research has emphasized the pivotal role that salespeople play in customer satisfaction. In this regard, the relationship between salespeople's attitudes, skills, and characteristics, and customer satisfaction remains an area of interest. The paper aims to make three contributions: first, it seeks to examine the impact of salespeople's satisfaction, adaptive selling, and dominance on customer satisfaction. Second, this research aims to use dyadic data, which is a better test of the relationships between constructs since it avoids common method variance. Finally, in contrast to previous research, it aims to test all of the customers of salespeople rather than customers selected by salespeople. Design/methodology/approach: The study employs multilevel analysis to examine the relationship between salespeople's satisfaction with the firm on customer satisfaction, using a dyadic, matched business-to-business sample of a large European financial service provider that comprises 188 customers and 18 employees. Findings: The paper finds that customers' evaluation of service quality, product quality, and value influence customer satisfaction. The analysis at the selling firm's employee level shows that adaptive selling and employee satisfaction positively impact customer satisfaction, while dominance is negatively related to customer satisfaction. Practical implications: Research shows that customer-focus is a key driver in the success of service companies. Customer satisfaction is regarded as a prerequisite for establishing long-term, profitable relations between company and customer, and customer contact employees are key to nurturing this relationship. The role of salespeople's attitudes, skills, and characteristics in the customer satisfaction process are highlighted in this paper. Originality/value: The use of dyadic, multilevel studies to assess the nature of the relationship between employees and customers is, to date, surprisingly limited. The paper examines the link between employee attitudes, skills, and characteristics, and customer satisfaction in a business-to-business setting in the financial service sector, differentiating between customer- and employee-level drivers of business customer satisfaction.

Role of the dsRNA-dependent protein kinase (PKR) in the attenuation of protein loss from muscle by insulin and insulin-like growth factor-I (IGF-I)

Proteolysis-inducing factor (PIF), a tumour-produced cachectic factor, induced a dose-dependent decrease in protein synthesis in murine myotubes, together with an increase in phosphorylation of eucaryotic initiation factor 2 (eIF2) on the alpha-subunit. Both insulin (1 nM) and insulin-like growth factor I (IGF-I) (13.2 nM) attenuated the depression of protein synthesis by PIF and the increased phosphorylation of eIF2alpha, by inhibiting the activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) by induction of protein phosphatase 1. A low-molecular weight inhibitor of PKR also reversed the depression of protein synthesis by PIF to the same extent, as did insulin and IGF-I. Both insulin and IGF-I-stimulated protein synthesis in the presence of PIF, and this was attenuated by Salubrinal, an inhibitor of phospho eIF2alpha phosphatase, suggesting that at least part of this action was due to their ability to inhibit phosphorylation of eIF2alpha. Both insulin and IGF-I also attenuated the induction of protein degradation in myotubes induced by PIF, this effect was also attenuated by Salubrinal. These results suggest an alternative mechanism involving PKR to explain the effect of insulin and IGF-I on protein synthesis and degradation in skeletal muscle in the presence of catabolic factors.

Export propensity, export intensity and firm performance:the role of the entrepreneurial founding team

We investigate how the characteristics and experience of the entrepreneurial founding team (EFT) affect the export orientation and subsequent performance of the businesses they establish, while allowing for the mutually reinforcing relationship between exporting and productivity. Using a sample of UK technology-based firms, we hypothesise and confirm that the set of EFT human capital needed for entering export markets is different from that required for succeeding in export markets. Commercial and managerial experience helps firms become exporters, but once over the exporting hurdle it is education, both general and specific, that has a substantially positive effect. The overall pattern of human capital effects on productivity is similar to those for export propensity. We also find evidence that productive firms are more likely both to enter export markets and to be export intensive, and that exporting boosts subsequent firm productivity.

Reinforcing the security of corporate information resources:a critical review of the role of the acceptable use policy

Increasingly users are seen as the weak link in the chain, when it comes to the security of corporate information. Should the users of computer systems act in any inappropriate or insecure manner, then they may put their employers in danger of financial losses, information degradation or litigation, and themselves in danger of dismissal or prosecution. This is a particularly important concern for knowledge-intensive organisations, such as universities, as the effective conduct of their core teaching and research activities is becoming ever more reliant on the availability, integrity and accuracy of computer-based information resources. One increasingly important mechanism for reducing the occurrence of inappropriate behaviours, and in so doing, protecting corporate information, is through the formulation and application of a formal ‘acceptable use policy (AUP). Whilst the AUP has attracted some academic interest, it has tended to be prescriptive and overly focussed on the role of the Internet, and there is relatively little empirical material that explicitly addresses the purpose, positioning or content of real acceptable use policies. The broad aim of the study, reported in this paper, is to fill this gap in the literature by critically examining the structure and composition of a sample of authentic policies – taken from the higher education sector – rather than simply making general prescriptions about what they ought to contain. There are two important conclusions to be drawn from this study: (1) the primary role of the AUP appears to be as a mechanism for dealing with unacceptable behaviour, rather than proactively promoting desirable and effective security behaviours, and (2) the wide variation found in the coverage and positioning of the reviewed policies is unlikely to be fostering a coherent approach to security management, across the higher education sector.